2,4-benzodiazepines

ABSTRACT

4,5-DIHYDRO-1H-2,4-BENZODIAZEPINES, E.G. THOSE OF THE FORMULA   3-R&#39;&#39;,(R)N-4,5-DIHYDRO-1H-2,4-BENZODIAZEPINE   R=H, ALKYL, FREE, ETHERIFIED OR ESTERIFIED OH OR SH, CF3, NO2 OR AMINO; N=1 OR 2 R&#39;&#39;=H, OH, SH, AMINO OR AN ALIPHATIC, ARALIPHATIC OR AROMATIC RADICAL ACYL DERIVATIVES, N-OXIDES, QUATERNARIES OR SALTS THEREOF, ARE ANTIHYPERTENSIVES AND INCREASE THE CONTRACTILE FORCE OF THE HEART.

United States Patent Office 3,696,093 Patented Oct. 3, 1972 US. Cl.260239 BD 8 Claims ABSTRACT OF THE DISCLOSURE4,5-dihydro-lH-2,4-benzodiazepines, e.g. those of the formula R-=*H,alkyl, free, etherified or esterified OH or SH, CF

N or amino; n=1 or 2 R' ='H, OH, SH, amino or an aliphatic, araliphaticor aromatic radical acyl derivatives, N-oxides, quatern'aries or saltsthereof,

are antihypertensives and increase the contractile force of the heart.

CROSS-REFERENCE TO RELATED APPLICATIONS This is a continuation-in-partof application Ser. No. 29,257, filed Apr. 16, 1970, which in turn is acontinuation-in-part of application Ser. No. 840,833, filed July 10,1969 (now abandoned), which in turn is a continuation-in-part ofapplication Ser. No. 694,421, filed Dec. 29, 1967 (now abandoned), whichin turn is a continuationin-part of application Ser. No. 630,497, filedApr. 13, 1967 (now abandoned).

SUMMARY OF THE INVENTIQN The present invention concerns and has for itsobject the provision of new 4,5-dihydrolH2,4-benzodiazepines, moreparticularly of those corresponding to Formula I Ii-N in which Ph is a1,2-phenylene radical, each of R and R are two hydrogens or aliphaticradicals; or one-hydrogen atom together with an aliphatic, araliphaticor aromatic radical, R is hydrogen hydroxy, mercapto, an amino group, analiphatic, araliphatic or aromatic radical and R is hydrogen, analiphatic, araliphatic or aromatic radical or the acyl radical of acarboxylic acid, of N-oX-ides, quaternaries and salts thereof, as wellas of corresponding pharmaceutical compositions and methods for thepreparation and application of these products. Said products are usefulcardiovascular agents, for example, in the treatment or management ofthe various forms of hypertension or of congestive heart failure.

DESCRIPTION OF THE PREFERRED EMBODIMENTS or i-propoxy or -butoxy,methylenedioxy, 1,1- or 1,2

ethylenedioxy, methylor ethylmercapto, or halogeno, such as fluoro,chloro or bromo, trifluoromethyl, nitro or amino, such as di-loweralkylamino, e.g. dimethylamino or diethylamino. The term lower, referredto above and hereinafter in connection with organic radicals orcompounds respectively, defines such with up to 7, preferably up to 4,carbon atoms. Preferred radicals Ph are 1,2 phenylene, (lower alkyl) 1,2phenylene, (lower alkoxy), 1,2 phenylene, (lower alkylmercapto) 1,2phenylene, (halogeno) 1,2 phenylene, (trifluoromethyl) 1,2 phenylene,(nitro) -l,2-phenylene or (di-lower alkylarnino) -1,2-phenylene, whereinn is the integer 1 or 2.

An aliphatic hydrocarbon radical mentioned for R to R is, for example,lower alkyl, e.g. that mentioned above, but also straight or branchedpentyl, hexyl or heptyl bound in any position, or lower alkenyl, e.g.allyl, methallyl or 3-butenyl. These radicals are preferablyunsubstituted, but may be substituted, for example by free or esterifiedhydroxy groups, for example, halogen atoms, such as hydroxyorhalogeno-lower alkyl, e.g. chloromethyl, 2-hydroxyor chloroethyl, or maybe interrupted by heteroatoms, preferably by one oxygen, sulfur and/ornitrogen atom, such as lower alkoxy-lower alkyl, e.g. methoxymethyl,ethoxymethyl, n-propoxymethyl, 1- 2- or 3-methoxy-, -ethoxyorn-propoxy-propyl or 4- tert. butoxy-butyl, the corresponding loweralkylmercapto-lower alkyl groups, monoor di-lower alkylaminolower alkyl,lower alkyleneimino-lower alkyl, aza-, oxaor thia-alkyleneimino-loweralkyl or N-lower alkylor phenyl-aza-alkyleneimino-lower alkyl groupswith preferably 4 to 6 ring-carbon atoms and in which radicalsheteroatoms are separated by at least two carbon atoms, such asdimethylaminomethyl, 2 methylamino-, 2 dimethylamino' or 2diethylamino-ethyl, 3 dimethylaminoor 3 diethylamino-propyl, 2pyrrolidino-ethyl, piperidinomethyl, 3 piperidino-propyl, 2piperazinoethyl, 2 (4 methyl-piperazino)-ethyl, 3 (4ethylpiperazino)-propyl, 2 (4 phenyl-piperazino)-ethyl, 2-morpholino-ethyl or 3 thiamorpholino-propyl.

An aromatic radical mentioned for R to R represents, for example,monocyclic isoor heterocyclic aryl, such as phenyl, pyridyl, thienyl,furyl, pyrryl, pyrazolyl or imidazolyl. They are unsubstituted orsubstituted by one or more than one of the same or differentsubstituents, e.g. those mentioned for Ph. Preferred aromatic radicalsare phenyl, (lower alkyl)-phenyl, (lower alkoxy)-phenyl, (loweralkylmercapto)-phenyl, (halogeno)-phenyl, (trifluoromethyl)-phenyl,(nitro)-phenyl or (di-lower alkylamino)-phenyl.

-An araliphatic radical mentioned for R to R is preferably monocyclicisoor heterocyclic aryl-lower alkyl or -alkenyl, such as benzyl, 1- or2-phenyl-ethyl, furfuryl, thenyl or cinnamyl, which may be substitutedas shown above.

An amino group R is unsubstituted or substituted, for example, by analiphatic, cycloaliphatic, araliphatic or aromatic radical, e.g. thosementioned above. It preferably is a secondary or tertiary amino group,for example, monoor di-lower alkylamino, lower alkenylamino, 3 to 6ring-membered cycloalkylamino or cycloalkyl-lower alkylamino, loweralkyleneimino or monoaza-, oxaor -thia-1ower alkleneimino, such asmonoor dimethylamino, mono or diethylamino, monoor di-nor i-propylamino;allylamino, methallylamino; cyclopropylamino, cyclopentyl amino, orcyclohexylamino; cyclopropylmethylamino or 2-cyclopentylethylamino;pyrrolidino piperidino, 1,4-pentyleneimino, 2,5- or 1,6-hexyleneirninoor 2,6-heptyleneimino; piperazino, N-lower alkyl-piperazino, morpholinoor thiamorpholino.

The carboxylic acid acyl radical R is, for example, lower alkanoyl, suchas acetyl, propionyl, butyryl or pivalyl.

The quaternaries of the invention are particularly those containingadditional lower alkyl or aralkyl groups, such as those mentioned above,quaternizing at least one tertiary nitrogen atom present.

The compounds of the invention exhibit valuable pharmacologicalproperties. Apart from coccidiostatic and some central nervous systemstimulating effects, they primarily exhibit antihypertensive effects andincrease the contractile force of the heart and its coronary blood flow.This can be demonstrated in animal tests using, for example, mammals orbirds, e.g. mice, dogs or chicken, as test objects. The coccidiostaticeffect can be demonstrated by the survival of chicken infected withsporulated oocysts of Eimeria terzella, but fed with a feed containingabout 0.01-0.1%, preferably about 0.05% of the compounds of theinvention. The central nervous system stimulation can be observed, forexample, in the jiggle cage test with mice at subcutaneous doses betweenabout and 100 mg./kg./day, preferably between about and 50 mg./kg./ day.The antihypertensive effects and the increase of the contractile forceof the heart are observed, for example, in unanesthetized renalhypertensive dogs or anesthetized dogs carrying a cardiac strain gaugerespectively, at doses between about 1 and 50 mg./kg./ day, preferablybetween about 5 and 25 mg./kg./day, applied either orally within gelatincapsules or in the form of aqueous solutions or suspensions into thelumen of the small intestine respectively. Accordingly, the compounds ofthe invention are preferably useful cardiovascular agents, for example,in the treatment or management of primary or secondary hypertension,e.g. essential or renal hypertension, or of congestive heart failure.Furthermore, the compounds of the invention are valuable intermediatesin the preparation of other useful products, particularly ofpharmacologically active compounds.

Particularly useful are compounds of Formula I, in which Ph is1,2-phenylene, (lower alkyl) -1,2-phenylene, (lower alkoxy)-l,2-phenylene, (lower alkylmercapto) 1,2-phenylene, (halogeno) 1,2phenylene, (trifiuoromethyl) -l,2-phenylene, (nitro) -1,2-phenylene or(dilower alkylamino),,-l,2-phenylene, n is the integer 1 or 2, each of Rand R are two hydrogens or hydrogen and lower alkyl, R -lower alkyl or RR is hydrogen, hydroxy, mercapto amino, monoor di-lower alkylamino,lower alkenylamino, 3 to 6 ring-membered cycloalkylamino orcycloalkyl-lower alkylamino, lower alkyleneimino, monoaza-, -oxaor-thia-lower alkyleneimino, lower alkyl, lower alkoxy-lower alkyl,halogeno-lower alkyl, di-lower alkylamino-lower alkyl, loweralkyleneimino-lower alkyl, monoaza-, -oxaor -thia-loweralkyleneimino-lower alkyl, in which heterocyclic radicals 2 heteroatomsare separated from each other by at least 2 carbon atoms, R -lower alkylor R R is hydrogen, lower alkyl, R -lower alkyl or lower alkanoyl, R isphenyl, (lower alkyl)-phenyl, (lower alkoxy)-phenyl, (loweralkylmercapto)-phenyl, (halogeno)-phenyl, (trifiuoromethyl)- phenyl,(nitro)-phenyl or (di-lower alkylamino)-phenyl, the N-oxide, loweralkylquaternaries or therapeutically useful acid addition salts thereof.

Compounds that are especially valuable are those of the Formulae II andIII III in which m is the integer 1 or 2, n is the integer 0 to 1, eachof R and R is hydrogen, methyl, methoxy, chloro, trifiuoromethyl ornitro and R" is hydrogen, hydroxy, mercapto, methoxy, amino, monoordimethylamino, monoor diethylamino, nor i-propylamino, allylamino,cyclopropylamino or piperidino or therapeutically useful acid additionsalts thereof which, when administered orally to unanesthetized renalhypertensive dogs or into a loop of the small intestine to anesthetizednormotensive dogs at doses between about 5 and about 25 mg./kg./day,show an outstanding decrease of elevated blood pressure and an increaseof the contractile force of the heart respectively (the latter ismeasured in /2 hour intervals with a cardiac strain gauge, sutured about1 hour before drug application onto the left ventricle of the heart).

Of particular interest are compounds of Formula III, in which m is theinteger l or 2, n is zero, R is hydrogen, methyl methoxy or chloro and Ris amino, methylamino, dimethylamino, ethylamino, nor i-propylamino,allylamino or cyclopropylamino, especially the 3-monoor dimethylamino4,5 dihydro-1H-2,4-benzodiazepine, the 7,8-dimethoxy derivative thereofor therapeutically useful acid addition salts of these compounds, whichare highly active antihypertensive and positive inotropic agents.

The compounds of the invention are prepared according to methods inthemselves known, for example, the corresponding process consists in (a)condensing a compound of the formula with a reactive functionalderivative of a carboxylic acid or (b) ring-closing a compound of theformula in which one of X and Y represents amino and the other amethylideneimino group and, if desired, converting a resulting compoundinto another compound of the invention.

A reactive functional derivative of a carboxylic acid is, for example,an ortho ester, imido ester, imido thioester, amidine or the nitrile ofan aliphatic, araliphatic or aromatic carboxylic acid or a reactivecarbonic acid derivative, such as O- or S-lower alkyl-isourea orisothiourea respectively, phosgene or diimidazolylcarbonyl.

The methylideneimino group present in the starting material mentionedunder item (b) is, for example, that formed in the condensation of acompound having the formula in which one of X and Y' stands for aminoand the other for potential amino, such as a nitro, azo or acylaminogroup, with the above-described reactive carboxylic acid derivatives. Inthe condensation product obtained, the potential amino group is thenconverted into amino, for example, by hydrogenation or hydrolysis,advantageously in an acidic medium. The following ring-closure ispreferably carried out with the free bases or in the presence of a basicagent, advantageously under pyrolytic conditions.

The compounds of the invention so obtained may be converted into eachother by known methods. Thus, for example, resulting compounds ofFormula I in which R is hydroxy or mercapto, may be etherified oresterified, for example with the-use of reactive esters or alcohols,e.g. lower alkyl halides, or reactive functional acid derivatives, e.g.thionyl halides or phosphorus oxyhalides. Resulting 3-esters, -ethers or-haloalkyl compounds may be reacted with ammonia or amines in order toobtain the 3-amino or -aminoalkyl compounds. Resulting carbonylcompounds or halophenyl compounds may be hydrogenated with catalyticallyactivated or nascent hydrogen, or with the use of complex light metalhydrides, such as lithium aluminum hydride or sodium borohydride inorder to obtain the corresponding methylene or unsubstituted phenylcompounds. Primary, secondary or tertiary amines may be converted intotertiary amines or quaternaries respectively, for example, with the useof reactive esters of corresponding alcohols, preferably lower alkanols,derived, for example, from hydrohalic or sulfonic acids, e.g.hydrochloric, hydrobromic, methane-, ethaneor p-toluenesulfonic acid.The N oxides of the invention are obtained, for example, by reacting thefree bases with hydrogen peroxide or a peracid, e.g. peracetic,perbenzoic or monoperphthalic acid.

The above-mentioned reactions are carried out according to standardmethods, in the presence or absence of diluents, preferably such as areinert to the reagents and are solvents thereof, of catalysts, condensingagents and/or inert atmospheres, at low temperatures, room temperatureor elevated temperatures, at atmospheric or superatmospheric pressure.

The compounds of the invention are obtained in the free form or in theform of their salts depending on the conditions under which the processis carried out; the salts are also included 'in the present invention.Salts that are obtained can be converted into the free bases in knownmanner, for example, with alkalis or ion exchangers. Free bases that areobtained can be converted into salts by reaction with inorganic ororganic acids, especially those that are suitable for the formation oftherapeutically useful salts. Such acids are, for example, hydrohalicacids, e.g. hydrochloric or hydrobromic acid, sulfuric, phosphoric,nitric or perchloric acid, aliphatic, alicyclic, araliphatic, aromaticor heterocyclic carboxylic or sulfonic acids, for example, formic,acetic, propionic, succinic, glycollic, lactic, malic, tartaric, citric,ascorbic, maleic, hydroxymaleic, pyroracemic, phenylacetic, benzoic,aminobenzoic, anthranilic, hydroxybenzoic, salicyclic, aminosalicyclic,embonic, nicotinic, methanesulfonic, ethanesulfonic,hydroxyethanesulfonic, ethylenesulfonic, halogenbenzenesulfonic,toluenesulfonic, naphthalenesulfonic and sulfanilic acid; methionine,tryptophan, lysine and arginine.

These or other salts, for example, the picrates, can also be used forthe purification of the bases obtained; the bases are converted intosalts, the salts are separated and the bases are liberated from thesalts. In view of the close relationship between the free compounds andthe compounds in the form of their salts, whenever a free base isreferred to in this context, a corresponding salt is also intended,provided such is possible or appropriate under the circumstances.

The invention further includes any variant of the present process, inwhich an intermediate product obtainable at any stage of the process isused as starting material and any remaining steps are carried out, orthe process is discontinued at any stage thereof, or in which thestarting materials are formed under the reaction conditions, or in whichthe reaction components are used in the form of their salts. Mainly,those starting materials should be used in the above reactions that leadto the formation of those compounds indicated as being speciallyvaluable.

The starting material used is known or, if new, may be preparedaccording to the methods illustrated in the examples. Thus, for example,that mentioned under item (a) may be prepared either by reduction ofcorresponding amides, nitriles or anhydrides and/or amination of thecorresponding alcohol derivatives, e.g. the hydrohalic or sulfonic acidesters. The preparation of the compounds shown under item (b) has beenmentioned above.

Starting material or final products that are mixtures of isomers may beseparated into single isomers by methods in themselves known. Forexample, compounds that contain one or more asymmetrical carbon atomsmay be in the form of racemate mixtures, pure racemates or opticalantipodes. Mixtures of racemates, by virtue of the physicochemicaldifferences between the components, can be resolved into pure racemates,for example, by chromatography and/ or fractional crystallization.Racemic products can likewise be resolved into the optical antipodes,for example, by reaction with optically active acids, separation of thediastereomeric salts and liberation of the bases from the salts.

The pharmacologically active compounds of the invention are useful inthe. manufacture of pharmaceutical compositions containing an effectiveamount thereof in conjunction or admixture with excipients suitable foreither enteral or parenteral application. Preferred are tablets andgelatin capsules comprising the active ingredient together with (a)diluents, e.g. lactose, dextrose, sucrose, mannitol, sonbitol, celluloseand/or glycine, (b) lubricants, e.g. silica, talcum, stearic acid, itsmagnesium or calcium salt and/or polyethyleneglycol, for tablets also(c) binders, e.g. magnesium aluminum silicate, starch paste, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose and/orpolyvinylpyrrolidone, if desired, ('d) disintegrants, e.g. starches,agar, alginic acid or its sodium salt, enzymes of the binders orefiervescent mixtures and /or (e) adsorbents, colorants, flavors andsweeteners. Injectable compositions are preferably aqueous isotonicsolutions or suspensions, and suppositories are advantageously fattyemulsions or suspensions. They may be sterilized and/or containadjuvants, such as preserving, stabilizing, wetting or emulsifyingagents, solution promoters, salts for regulating the osmotic pressureand/or buffers. They may also contain other therapeutically valuablesubstances. Said pharmaceutical compositions are prepared according toconventional mixing, granulating or coating methods respectively andcontain about 0.1 to 75%, preferably about 1 to 50% of the activeingredient.

The following examples illustrate the invention and are not to beconstrued as being limitations thereon. Temperatures are given incentigrade and all parts given are parts by weight.

EXAMPLE 1 To the solution of 2.0 g. of 1,2-bis-aminomethyl-benzene in 40ml. ethanol, 1.78 g. acetimidic acid ethyl ester hydrochloride are addedand the mixture is refluxed for 16 hours. Hereupon it is evaporated toabout of the original volume and allowed to stand at room temperaturefor 2 hours. The precipitate is filtered off, washed with diethyl etherand dried to yield the 3-methyl-4,5-

dihydro-1H-2,4-benzodiazpine hydrochloride of the formelting at 283 withdecomposition.

The starting material is prepared as follows: 4.0 g.1,2-bis-aminomethyl-benzene dihydrochloride are dissolved in 10 ml.water and the solution is made basic with aqueous sodium hydroxide to apH of about 12. The mixture is extracted twice with 75 ml. chloroformeach, the combined extract washed with 10 ml. water, dried andevaporated to yield the corresponding free amine.

EXAMPLE 2 To the solution of 4.0 g. l,Z-bis-aminomethyl-benzene in 100ml. ethanol, 5.6 g. phenyl-acetimidic acid ethyl ester hydrochloride areadded and the mixture is refluxed for 16 hours. Hereupon it isconcentrated to about 25 ml. and allowed to stand at room temperaturefor two hours. It is filtered, the residue washed with diethyl ether anddried to yield the 3-benzyl-4,5-dihydro-1H-2,4-benzodiazpinehydrochloride of the formula melting at 256-259 with decomposition.

EXAMPLE 3 To the solution of 5.0 g. 1,Z-bis-aminomethyl-benzene in 125ml. ethanol, 8.1 g. 4-chloro-benzimidic acid ethyl ester hydrochlorideare added and the mixture is refluxed for 16 hours. It is allowed tocool and the precipitate formed filtered off, washed with diethyl etherand recrystallized from ethanol to yield the 3-(4-chloro-phenyl)4,5-dihydro-lH-2,4-benzodiazepine hydrochloride of the formula meltingat 266-267".

EXAMPLE 4 The mixture of 2.0 g. 1,Z-bis-aminomethyl-benzene, 5.6 g.methoxyacetimidic acid ethyl ester hydrochloride and 125 ml. ethanol isrefluxed for 16 hours. After cooling 1 liter diethyl ether are addedwhile stirring. The precipitate formed is filtered off andrecrystallized from n-butanol to yield the3-methoxymethyl-4,5-dihydro-1H- 2,4-benzodiazepine hydrochloride of theformula melting at 175-178".

EXAMPLE 5 To the solution of 6.0 g. 1,2-bis-aminomethyl-benzene in 150ml. tetrahydrofuran, that of 7.5 g. N,N'-diimidazolyl-carbonyl in 100ml. tetrahydrofuran is slowly added while stirring and ice-cooling. Themixture is allowed to stand at room temperature overnight, theprecipitate formed is filtered off and washed with tetrahydrofuran, toyield the 3-hydroxy-4,5-dihydro-lH-2,4-benzodiazepine of the formulamelting above 300; in the IR. spectrum it shows bands inter alia at3115, 1595, 1485, 1390, 1340, 1265 and 1195 cm.-

EXAMPLE 6 T0 the solution of 2.0 g. 1,2-bis-aminomethyl-benzene in 25ml. methanol, 2.3 g. chloracetimidic acid ethyl ester hydrochloride areadded and the mixture allowed to stand overnight. It is then addeddropwise to a large volume of diethyl ether while stirring and theprecipitate formed is filtered off to yield the3-chlor0methyl-4,5-dimelting at 263-264".

The solution of 10 g. thereof in the minimum amount of water is madebasic with sodium hydroxide to a pH of about 9. The precipitate formedis filtered off, washed with water, dried and recrystallized from ethylacetate to yield the corresponding base melting at 235-240".

The starting material is prepared as follows: The mixture of 500 g.1,2-bis-bromomethyl-benzene, 1 kg. potassium phthalimide and 3.78 It.dimethylformamide is refluxed for 16 hours while stirring. It is cooledto about diluted with an equal volume of water, the precipitate formedfiltered off, washed with water, ethanol and diethyl ether to yield the1,Z-bis-phthalimidomethyl-benzene melting at 275 To the mixture of 200g. thereof and 7 1t. n-butanol, 48.5 ml. hydrazine hydrate are added andthe mixture is refluxed for 16 hours while stirring. Hereupon 100 m1.concentrated hydrochloric acid are added and refluxing is continued for24 hours. The mixture is concentrated to about /2 of its volume invacuo, the precipitate formed filtered off and triturated with 500 ml.water. The aqueous solution is evaporated in vacuo and the residuetriturated with methanol to yield the 1,2-bis-aminomethylbenzenedihydrochloride melting above 300 after recrystallization from aqueousethanol.

EXAMPLE 7 To 50 ml. of a saturated solution of dimethylamine inmethanol, 4.5 g. 3-chloromethyl-4,5-dihydro-1H-2,4- benzodiazepine areadded and the mixture refluxed for /2 an hour. It is cooled, acidifiedwith ethanolic hydrochloric acid and the precipitate formed filtered offto yield the 3-dimethylaminomethyl-4,S-dihydro-1H-2,4-benzodiazepinedihydrochloride of the formula CHzN(CHa)2-2HCl melting at 239-241.

EXAMPLE 8 The mixture of 7.5 g.3-hydroxy-4,5-dihydro-1H-2,4-benzodiazepine and 30 ml. phosphorusoxychloride is heated at the steam bath for 3 hours while stirring. Itis evaporated in vacuo, the residue triturated with ethyl acetate, thesolid filtered off and added portionwise to 200 ml. liquid ammonia. Themixture is stirred and allowed to evaporate at room temperature duringabout 3 hours. The residue is taken up in water, the solution madestrongly basic with saturated aqueous potassium hydroxide and extractedwith chloroform. The extract is dried, filtered and evaporated. Theresidue is taken up in ethanol, the solution acidified with ethanolichydrochloric acid, the precipitate formed filtered off andrecrystallized from ethanol-methanol to yield the3-amino-4,5-dihydro-lH-2,4- benzodiazepine hydrochloride of the formulamelting at 279-281".

EXAMPLE 9 To the filtrate obtained from the mixture of 20 g. imidazole,350 ml. tetrahydrofuran and the solution of 8.6 g. thiophosgene in 50ml. tetrahydrofuran, the solution of 10 g. 1,Z-bis-aminomethyl-benzenein 50 ml. tetrahydrofuran is added dropwise while stirring. The mixtureis refluxed overnight, cooled, filtered and the residue washed withtetrahydrofuran to yield the 3-mercapto-4,5-dihydro-1H-2,4-benzodiazepine of the formula melting at 283-284".

EXAMPLE 10 To the solution of 25 ml. piperidine in 20 ml. methanol, 10g. 3-chloromethyl-4,5-dihydro-lH-2,4-benzodiazepine are added and themixture is stirred overnight. It is diluted with toluene and evaporatedin vacuo. The residue is dissolved in aqueous ethanol, the solution madebasic with aqueous sodium hydroxide, extracted with chloroform and theextract dried, filtered and evaporated. The residue is dissolved inethanol, the solution acidified with ethanolic hydrochloric acid, theprecipitate formed filtered off and washed with diethyl ether to yieldthe 3-piperidinomethyl- 4,5-dihydro-1H-2,4-benzodiazepinedihydrochloride of the formula -CHz'N 2H0] melting at 288289.

EXAMPLE 11 The mixture of 1.0 g. 3-(4-chloro-phenyl)-4,5-dihydro-1H-2,4-benzodiazepine hydrochloride, 100 ml. anhydrous ethanol and 0.2g. palladium on charcoal is hydrogenated at 25 p.s.i. for 3 hours atroom temperature. It is filtered, the filtrate diluted with diethylether and the precipitate formed filtered ofi to yield the 3-phenyl-4,5-dihydro-1H-2,4-benzodiazepine hydrochloride of the formula -o,H5-H01 a.)

melting at 232234.

EXAMPLE 12 In the manner described in the previous examples thefollowing compounds of Formula II are prepared from equivalent amountsof the corresponding starting material; they are monohydrochlorides andwere recrystallized from ethanol:

R6: M-P. 4-NO -C H 278-280 3-NO -C H 260 4-CF -C H Above 300 EXAMPLE 13Preparation of 10,000 tablets each containing mg. of the activeingredient.

Material: G.

3-amino-4,5-dihydro-1H-2,4 benzodiazepine hydrochloride 1,000.0 Lactose2,535.0 Talcum powder 150.0 Magnesium stearate 40.0 Corn starch 125.0Polyethylene glycol 6,000 150.0

Purified water, q.s.

Procedure All the powders are passed through a screen with an opening of0.6 mm. Then the drug substance, lactose, talcum, magnesium stearate and/2 of the starch are mixed in a suitable mixer. The other /2 of thestarch is suspended in 50 ml. water and the suspension added to the hotsolution of the polyethylene glycol in 180 ml. water. The paste formedis added to the powders, which are granulated, if necessary, with anadditional amount of water. The granulate is dried overnight at 35,broken on a screen with 1.2 mm. opening and compressed into tabletsusing concave punches with 10.3 mm. diameter, uppers bisected.

In the analogous manner, tablets are prepared using 50450 mg. of thecompounds described in Examples 1-6.

EXAMPLE 14 To the solution of 5.0 g. 1,Z-bis-aminomethyl-benzene in ml.ethanol, 7.9 g. 4-methoxy-benzimidic acid ethyl ester hydrochloride areadded and the mixture refluxed overnight and then kept in therefrigerator for 6 hours. The precipitate formed is filtered 01f, washedwith diethyl ether and recrystallized from ethanol to yield the 3-(4-methoxy-phenyl) 4,5 dihydro lH-2,4 benzodiazepine hydrochloride of theformula melting at 262-263 EXAMPLE 15 The solution of 2.0 g.3-phenyl-4,5-dihydro-1H-2,4- benzodiazepine hydrochloride (Example 11)in the minimum amount of water is made basic with aqueous potassiumhydroxide and extracted with chloroform. The extract is dried, filteredand evaporated. The residue is taken up in ethanol, the solutionslightly acidified with ethanolic maleic acid, the precipitate formedfiltered off and recrystallized from ethanol, to yield the3-phenyl-4,5-dihydro- 1H-2,4-benzodiazepine maleate of the formula(EH-000E (EH-C0011 melting at 19l193.

1 1 EXAMPLE 16 The mixture of 7.5 g. 3-hydroxy-4,5-dihydro-1H-2,4-benzodiazepine and 30 ml. phosphorus oxychloride is heated at the steambath for about 3 hours while stirring and then evaporated in vacuo. Tothe residue the solution of ml. methylamine in 100 ml. tetrahydrofuraneis added and the mixture stirred at room temperature overnight. It isevaporated in vacuo, the residue taken up in water, the mixture madealkaline with aqueous potassium hydroxide and extracted with chloroform.The extract is dried, filtered, and evaporated. The residue is taken upin ethanol, the solution acidified with ethanolic hydrochloric acid, theprecipitate formed filtered off and recrystallized from ethanol, toyield the 3-methylamino-4,5-dihydro-1H- ethanol, the solution acidifiedwith ethanolic hydrochloric 2,4-benzodiazepine hydrochloride of theformula melting at 210-211.

In the analogous manner the3-dimethylamino-4,5-dihydro-lH-2,4-benzodiazepine hydrochloride isprepared from the same amounts of the corresponding starting material;it melts at 252- 6.

EXAMPLE 17 Preparation of 10,000 tablets each containing 50.0 mg. of theactive ingredient:

Formula: G.

3-methylamino 4,5-dihydro 1H-2,4-benzodiazepine hydrochloride 500.00

Lactose 1,706.00

Corn starch 90.00 Polyethylene glycol 6,000 90.00 Talcum powder 90.00Magnesium stearate 24.00

Purified water, q.s.

Procedure All the powders are passed through a screen with an opening of0.6 mm. Then the drug substance, lactose, talcum, magnesium stearate andhalf of the starch are mixed in a suitable mixer. The other half of thestarch is suspended in 45 ml. water and the suspension added to theboiling solution of the polyethylene glycol in 180 ml. water. The pasteformed is added to the powders which are granulated, if necessary, withan additional amount of water. The granulate is dried overnight at 35,broken on a screen with 1.2 mm. openings and compressed into tabletsusing concave punches with 7.1 mm. diameter, uppers bisected.

Analogous tablets can be prepared using the 3-methyl-,3-piperidinomethy1- or 3-dimethylamino-4,S-dihydro-1H-2,4-benzodiazepine hydrochlorides of Examples 1, 10 and 16 as drugsubstances.

EXAMPLE 18 The solution of 9.0 g. N-(2-aminomethyl-benzyl)-acetamidinein 100 ml. ethanol is refluxed for 24 hours. It is cooled, acidifiedwith ethanolic hydrochloric acid and evaporated in vacuo. The residue istriturated with diethyl ether and recrystallized from ethanol, to yieldthe 3- methyl-4,5-dihydro-lH-2,4-benzodiazepine hydrochloride melting at283 with decomposition; it is identical with the compound obtainedaccording to Example 1.

The starting material is prepared as follows: The mixture of 500 g.1,2-bis-bromomethyl-benzene, 500 g. potassium phthalimide and 3.78liters dimcthylformamide is refluxed for 10 hours While stirring andconcentrated in vacuo. The precipitate formed after cooling is filteredoff and recrystallized from aqueous ethanol, to yield the 2-phthalimidomethyhbenzyl bromide.

To the solution of g. thereof in 1 liter dimethylsulfoxide, 57 g. sodiumnitrite are added portionwise and the mixture is stirred for 10 hours at50. It is diluted with water, the precipitate formed filtered ofl",washed with water, ethanol and diethyl ether and recrystallized fromethanol dimethylforrnamide, to yield thel-nitromethyl-2-phthalimidomethyl-benzene.

The mixture of 20 g. thereof and 100 ml. concentrated hydrochloric acidis heated in a sealed tube for 3 hours to It is cooled, filtered, theresidue washed with Water and the filtrate made basic with aqueoussodium hydroxide. It is dried, extracted with chloroform, the extractfiltered, evaporated in vacuo, and the residue recrystallized fromaqueous ethanol to yield the 2-nitromethyl-benzylamine.

To the solution of 10 g. thereof in 50 ml. ethanol, 7.5 g. acetimidicacid ethyl ester hydrochloride are added and the mixture is refluxed for3 hours. It is concentrated in vacuo, the precipitate formed filteredoff, dissolved in the minimum amount of water and the solution madebasic with aqueous potassium hydroxide. It is extracted with chloroform,the extract dried, filtered and evaporated in vacuo, to yield theN-(2-nitromethylbenzyl)- acetamidine.

12 g. thereof are hydrogenated in 100 ml. ethanol over 1 g. platinumoxide at an initial pressure of 45 p.s.i. at room temperature. After theuptake of the theoretical amount of hydrogen, the mixture is filtered,and evaporated in vacuo, to yield the N-(Z-aminomethyl-benzyl)-acetamidine, which is used as such without further purification.

EXAMPLE 19 To 75 ml. liquid ethylamine, 15 g.3-chloro-4,5-dihydro-lH-2,4-benzodiazepine (prepared according toExample 8) are added portionwise while stirring and cooling with a DryIce-acetone bath. After stirring overnight and allowing the temperatureto rise to room temperature, the concentrate is diluted with 100 ml.methanol and added to the solution prepared from 3.1 g. sodium and 100ml. methanol While stirring. After V2 hour, the mixture is filtered, thefiltrate evaporated in vacuo below 40 and the residue taken up indiethyl ether. The solution is filtered, the filtrate evaporated, theresidue taken up in the minimum amount of warm isopropanol, the solutionneutralized with hydrogen chloride in ethyl acetate, the precipitateformed filtered off and recrystallized from isopropanol, to yield the3-ethylamino-4,5-dihydro- 1H-2,4-benzodiazepine hydrochloride of theformula N O unczrn-noi melting at 209-212".

EXAMPLE 20 To 100 ml. n-propylamine, 15 g. 3-chloro-4,5-dihydrolH-2,4-benzodiazepine are added portionwise while stirring and coolingwith Dry Ice-acetone. Hereupon, the cooling is discontinued and themixture stirred overnight at room temperature. It is evaporated invacuo, the residue taken up in 100 ml. methanol, the mixture combinedwith the solution prepared from 3.1 g. sodium and 100 ml. methanol andthe whole stirring for /2 hour at room temperature. After evaporation invacuo, the residue is triturated with acetonitrile, filtered and thefiltrate evaporated in vacuo. The residue is taken up in isopropanol,the solution neutralized with hydrogen chloride in ethyl acetate, theprecipitate formed filtered off and recrystallized from water, to yieldthe 3-n-propylamino-4,5-dihydro-1H-2,4-benzodiazepine hydrochloridemonohydrate of the formula melting at 78-80.

EXAMPLE 21 To the solution of 2.4 g. sodium methoxide in 100 ml.methanol, 4.8 g. 1,2-bis-aminomethyl-3-methyl-benzene dihydrochlorideare added portionwise while stirring. After stirring for 1 hour at roomtemperature, the mixture is filtered, the filtrate evaporated in vacuo,the residue triturated with acetonitrile, the mixture filtered and thefiltrate evaporated in vacuo. The residue is taken up in 50 ml.tetrahydrofuran and 4.0 g. N,N-diimidazolylcarbonyl are added dropwisewhile stirring, and stirring is continued for 24 hours at roomtemperature. The precipitate formed is filtered off and washed with coldtetrahydrofuran, to yield the3-hydroxy-6-methyl-4,5-dihydro-1H-2,4-benzodiazepine of the formula Non, H

showing in the LR. spectrum bands at 3440, 1640 and 750 cmr The startingmaterial is prepared by bromination of hemimellitene, separation of the1,2-bis-bromomethyl-3- methylbenzene from the reaction mixture byfractional distillation under reduced pressure, and its aminationaccording to Example 6.

EXAMPLE 22 The hot solution of 7.8 g. sodium methoxide in 1 litermethanol is slowly added to 16 g. 1,2-bi s-aminomethylbenzenedihydrochloride hemihydrate while stirring, and stirring is continuedfor /2 hour. The mixture is filtered through a fritted glass funnel andthe filtrate evaporated in vacuo. The resulting semi-solid free base istriturated with diethyl ether, filtered again, and the filtrateevaporated. The residue is taken up in 200 ml. n-butanol, 18 g. 1,2,3trimethyl 2 thiopseudourea hydroiodide are added (the mixture refluxedfor 24 hours and evaporated in vacuo, to yield the3-methylamino-4,5-dihydro-1H-2,4- benzodiazepine hydroiodide of theformula melting at 175. It is taken up in 500- ml. methanol, 7.2 g.freshly prepared silver chloride are added and the suspension is stirredfor /2 hour at room temperature. It is filtered, the filtrate evaporatedin vacuo and the residue recrystallized from isopropanol, to yield thecorresponding hydrochloride melting at 214-216"; it is identical, butsomewhat purer, than that obtained according to Example 16.

EXAMPLE 23 To the mixture of 31.2 g. sodium methoxide and 400 ml.methanol, 64 g. l,Z-bis-aminomethyl-benzene dihydrochloride are addedportionwise while stirring. After /2' hour, the mixture is filtered, theresidue washed with methanol and the filtrate evaporated. The residue istaken up in 800 ml. n-butanol, 87.5 g. 1,3-dicyclopropyl-2-methyl-Z-thiopseudourea hydroiodide are added and the mixture refluxedfor 4 days. It is evaporated in vacuo, the residue taken up in 1 litermethanol, 29 g. freshly prepared silver chloride are added and thesuspension stirred for 1 hour at room temperature. It is filtered, thefiltrate evaporated in vacuo and the residue recrystallized fromethanol-acetonitrile, to yield the 3-cyclopropylamino 4,5 dihydro 1H 2,4benzodiazepine hydrochloride of the formula @ijymq .1...

melting at 195-198".

The starting material is prepared as follows: To the solution of 65 g.cyclopropylamine in 500 ml. tetrahydrofuran, the mixture of 35 g.thiophosgene and ml. tetrahydrofuran is added dropwise while stirringand stirring is continued for 2 hours at room temperature. The mixtureis filtered, the filtrate evaporated in vacuo and the residue trituratedwith ethyl acetate, to yield the 1,3- dicyclopropyl-thiourea.

The mixture of 27 g. thereof, 40 g. methyliodide and 200 ml. methanol isallowed to stand at room temperature for 1 hour and at the steam bathfor 1 hour. It is evaporated in vacuo and the residue recrystallizedfrom ethyl acetate-acetonitrile, to yield the l,3-dicyclopropyl2-methyl-2-thiopseudoureahydroiodide melting at 146- 149.

In the analogous manner, the 3-isopropylamino-4,5-dihydro-1H-2,4-benzodiazepine hydrochloride is prepared, M.P. 196-198";its hydroiodide melts at 25l-254.

EXAMPLE 24 The mixture of 12 g. 1,3-diallyl-thiourea, 15 g. methyliodideand 100 ml. methanol is heated at the steam bath melting at -171.

EXAMPLE 25 The mixture of 18.7 g. 1,2 bis aminomethyl 4,5-dimethoxybenzene, 26 g. 1,2,3 trimethyl 2 thiopseudourea hydroiodide and360 ml. n-butanol is refluxed for 48 hours. It is evaporated in vacuo,the residue taken up in the minimum amount of methanol, 15 g. freshlyprepared silver chloride are added and the suspension stirred for 1 hourat room temperature. It is filtered, the filtrate evaporated in vacuo,the residue recrystallized from isopropanol and dissolved in the minimumamount of water. The solution is made basic with 2 N aqueous sodiumhydroxide, extracted with diethyl ether, the extract dried, filtered andevaporated. The residue is taken up in ethanol, the solution acidifiedwith ethanolic hydrogen chloride, diluted with isopropanol and theprecipitate formed filtered 01f, to yield the 3 methylamino- NIICII3 HO]CHsO melting at 257-260.

The starting material is prepared as follows: Through 320 ml. 37.5%aqueous formaldehyde, hydrogen chloride is bubbled for 45 minutes at15-20", whereupon 32 g. veratric acid are added and the mixture stirredfor 7 hours at about 65 It is allowed to stand overnight at roomtemperature, evaporated in vacuo and the residue taken up in 250 ml.water. The solution is neutralized with aqueous ammonia, filtered andthe residue washed with water, to yield the 4,5-dimethoxy-phthalide,melting at 154-156".

The solution of 19.4 g. thereof in 400 ml. tetrahydrofuran is addeddropwise to the suspension of 3.8 g. lithium aluminum hydride and 100ml. tetrahydrofuran while while stirring at 0-5 under nitrogen. Afterstirring for 3% hours at room temperature, the mixture is refluxed for 5hours and stirred overnight at room temperature. It is cooled in an icebath, ml. water are added dropwise while stirring, the mixture filteredand the filtrate evaporated in vacuo. The residue is recrystallized fromethyl acetate, to yield the 1,2 bis hydroxymethyl 4,5- dimethoxybenzenemelting at 108-111.

The mixture of 9.9 g. thereof and ml. thionylchloride is stirred at roomtemperature overnight and evaporated, to yield the 1,2 bis chloromethyl4,5 dimethoxybenzene melting at 90.

10 g. thereof are added to the mixture prepared from 6 g. 57% sodiumhydride in mineral oil, 17.7 g. phthalimide and ml. dimethoxyformamidewhile cooling and stirring under nitrogen. The mixture is refluxed for 1/2 hours, cooled and ml. water are added. The precipitate formed isfiltered off, washed with water, acetone and diethyl ether, to yield the1,2-bis-phthaliminomethyl- 4,5-dimethoxy-benzene melting at .257260.

To the mixture of 22.7 g. thereof and 500 ml. nbutanol, 4.7 ml. 99%hydrazine hydrate are added dropwise while stirring and the mixturerefluxed for 16 hours. Hereupon 10 ml. concentrated hydrochloric acidare added and refluxing is continued for 24 hours. The mixture isevaporated in vacuo, the residue taken up-in ml. water, the solutionfiltered, the filtrate evaporated in vacuo and the residuerecrystallized from aqueous isopropanol, to yield the1,2-bis-aminomethyl-4,S-dimethoxybenzene dihydrochloride, melting at299. It is converted into the free base as described in Example 22.

EXAMPLE 26 To the solution of 10.8 g. sodium methoxide in 200 ml.methanol, 22.3 g. 1-aminomethyl-2-methylaminomethylbenzenedihydrochloride are added while stirring. After 4 hours the mixture isfiltered, the filtrate concentrated in vacuo and the concentratetriturated with diethyl ether. The additional solid formed is discarded,and the filtrate evaporated in vacuo, to yield a strongly basic oil. Itis dissolved in 500 ml. n-butanol, 12.0 g. acetimidic acid ethyl esterare added and the solution is refluxed for 24 hours. After coolingovernight it is filtered and the residue recrystallized from isopropanolto yield the 3,4-dimethyl- 4,5-dihydro1H-2,4-benzodiazepinehydrochloride of the formula showing I.R.-bands at 3134, 3120 and 1665cmf The starting material is prepared in the following manner: Throughthe solution of 57.0 g. Z-phthalimidomethylbenzyl bromide (Example 18)in 200 m1. dimethylformamide, methylamine gas is bubbled while cooling,to maintain room temperature. After saturation is complete, the solutionis allowed to remain at room temperature overnight. It is evaporated invacuo, the residue suspended in 200 ml. concentrated hydrochloric acidand the suspension refluxed overnight While stirring. It is cooled inice, filtered and the filtrate concentrated in vacuo. The concentrate ismade strongly basic with solid sodium hydroxide, the solution extractedwith diethyl ether, the extract washed with brine, dried and evaporatedin vacuo. The residual oil is dissolved in 500 ml. ethanol, the solutionmade acidic with ethanolic hydrogen chloride, the solid formed filteredoff and recrystallized twice from ethanol, to yield the1-aminomethyl-2-methylaminomethylbenzene dihydrochloride.

EXAMPLE 27 showing I.R.-bands at 3127 and 1678 cmr EXAMPLE 28 To thesolution of 1.85 g. 4-chloro-5-methyl-1,2-bisaminomethylbenzene in 30ml. absolute ethanol, 1.20 g. acetimidic acid ethyl ester are added andthe solution is refluxed for 18 hours. After cooling in ice overnight,the precipitate formed is filtered off and recrystallized fromisopropanol-acetonitrile, to yield the7-chloro-3,8-dimethyl-4,5-dihydro-1H-2,'4 benzodiazepine hydrochlorideof the formula showing I.R.-bands at 3130 and 1682 cmr EXAMPLE 29 To thesolution of 3.0 g. 3-methyl-4,5-dihydro-lH-2,4- benzodiazepine in 50 ml.dimethylformamide, 1 g. potassium carbonate and 5 ml. methyl iodide areadded and the mixture is heated in a sealed tube to 150 for 5 hours.After cooling it is filtered, the filtrate evaporated in vacuo and theresidue recrystallized from a small volume of hot water, to yield the3,4-dimethyl-4,5-dihydro-1H-2,4-benzodiazepine methiodide of the formulashowing a strong I.R.-band at 1620 cmf in which Ph is unsubstituted1,2-phenylene or 1,2-phenylene substituted by up to two members of thegroup consisting of lower alkyl, hydroxy, mercapto, lower alkoxy, loweralkylenedioxy, lower alkylmercapto, halogeno, trifluoromethyl, nitro,amino or di-lower alkylamino, each of R and R are two hydrogen atoms orone hydrogen atom and one member of the group consisting of lower alkyl,R -lower alkyl or R wherein R is phenyl, (lower alkyl)-phenyl, (loweralkoxy)-phenyl, (lower alkylmercapto) phenyl, (halogeno) phenyl,(trifluoromethyD- phenyl, -(nitro)-pheny1 or (di-loweralkylamino)-phenyl, R is hydrogen, hydroxy, mercapto, amino, monoordilower alkylamino, lower alkyleneimino, piperazino, N- loweralkyl-piperazino, morpholino or thiamorpholino, lower alkyl, loweralkoxy-lower alkyl, halogeno-lower alkyl, di-lower alkylamino-loweralkyl, lower alkyeneimino-lower alkyl, (piperazino, N-loweralkyl-piperazino, morpholino or thiamorpholino)-lower alkyl, R -loweralkyl or R and R is hydrogen, lower alkyl, R -lower alkyl or loweralkanoyl, the N-oxide, lower alkyl quaternaries or therapeuticallyuseful acid addition salts thereof.

2. A compound as claimed in claim 1 and corresponding to the formula inwhich n is the integer 0 or 1 and each of R and R is hydrogen, methyl,methoxy, chloro, trifluoromethyl or nitro, or a therapeutically usefulacid addition salt thereof.

3. As compound as claimed in claim 1 and corresponding to the formula(CH1),,R"

in which m is the integer 1 or 2, n is the integer 0 or 1, R ishydrogen, methyl, methoxy, chloro, trifiuoromethyl or nitro and R" ishydrogen, hydroxy, mercapto, methoxy, amino, monoor dimethylamino,monoor diethylamino, nor i-propylamino, or piperidino, or atherapeutically useful acid addition salt thereof.

4. A compound as claimed in claim 3, in which formula m is the integer 1or 2, n is zero, R is hydrogen, methyl, methoxy or chloro and R" isamino, methylamino, dimethylamino, ethylamino, nor i-propylamino,allylamino or cyclopropylamino, or a therapeutically useful acidaddition salt thereof.

5. A compound as claimed in claim 3 and being the3-methylamino-4,5-dihydro-1H 2,4 benzodiazepine or a therapeuticallyuseful acid addition salt thereof.

6. A compound as claimed in claim 3 and being the3-dimethylamino-4,5-dihydro-lH-2,4-benzodiazepine or a therapeuticallyuseful acid addition salt thereof.

7. A compound as claimed in claim 3 and being the3-methylamino-7,8-dimethoxy 4,5 dihydro-lH-2,4-benzodiazepine or atherapeutically useful acid addition salt thereof.

8. A compound as claimed in claim 3 and being the3-methylamino-4,S-dihydro-1H-2,4-benzodiazepine hydrochloride.

References Cited Sternbach: The Chemistry of Benzodiazepines, Chem.Reviews, vol. 68, p. 783 (1968).

ALTON D. ROLLINS, Primary Examiner US. Cl. X.R.

260-239 A, 239 E, 243 B, 247.1, 247.2 A, 247.5 B, 268 BC, 293.59, 295.5S, 296 B, 309, 310 R, 326 N, 326.3, 326.5 S, 326.5 CA, 326.81, 326.9 329F, 340.3, 340.5, 347.7; 424--244, 246, 248, 250, 267, 274

T323? UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3, 9 93 Dated October 3, 1972 Inventor(s) RODRIGUEZ ET AL It iscertified that error appears in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below:

Column 18, claim 3, line 5, amend the right side of the structuralformula to read:

Signed and sealed this ll th dey "of May 197 4;

(SEA L) Attest:

EDWARD TLFLETCT-TEEJR. c. MARSHALL DANN Attesting Officer Commissionerof Patents

